Background and goals: Many older adults in the US use prescription opioid medications long-term for chronic pain. There are major gaps in our knowledge about opioid safety, including long-term effects on cognition. Dementia and cognitive decline are among the most feared conditions associated with aging. There is evidence that opioids may harm brain function: studies have found Alzheimer's Disease-like changes in the brains of young drug abusers who use narcotics, and opioids cause programmed cell death in microglia (brain immune cells) and neurons. But no prior epidemiologic study has examined late-life brain outcomes in relation to prescription opioid use. Our goal is to leverage existing epidemiologic data to study the associations of opioid use with outcomes including dementia and Alzheimer's Disease. Methods: We will use data from the Adult Changes in Thought (ACT) prospective cohort study, which since 1994 has enrolled nearly 4500 community-dwelling older adults. Participants who screen positive for possible dementia at biennial study visits undergo thorough clinical evaluation, and a multidisciplinary consensus committee determines dementia status using standardized research criteria. Over 29,000 person-years of follow-up, 841 participants have developed dementia and 414 have undergone autopsy. ACT is set within an integrated health care system with computerized pharmacy data going back to 1977, which makes it possible to study brain outcomes in relation to use of many prescription medications. We previously studied dementia and neuropathologic changes associated with use of nonsteroidal anti-inflammatory drugs, the major therapeutic alternative to opioids. Now we propose to use ACT data to address the following aims: Aim 1: Determine whether higher cumulative, long-term opioid use is associated with a) higher risk of all-cause dementia or Alzheimer's Disease; b) more rapid decline in global cognitive functioning; and c) higher burden of Alzheimer's Disease neuropathology (e.g. neuritic plaques, neurofibrillary tangles). Aim 2: Determine the relationships of current or recent vs. distant opioid use with a) risk of all cause dementia or Alzheimer's Disease and b) global cognitive functioning. Impact: This research will provide new information about the association of prescription opioid use with late- life brain outcomes including dementia and Alzheimer's Disease. Our findings will be important to patients and their providers who are making decisions about long-term opioid use for chronic pain. PUBLIC HEALTH RELEVANCE: Many older adults take opioid pain medications long-term, but there is little information about the safety of these medications, including whether they harm brain function. No prior studies have examined late-life brain outcomes such as dementia, overall cognitive function, or microscopic changes in the brain in relation to opioid use. The study would fill this critical knowledge gap, and findings could immediately be used by patients and their providers who are making decisions about using opioids long-term for chronic pain.